Defects in vasculogenesis (early retinal vessel development) seem to be mediated through the Norrin-dependent Wnt signaling pathway. Norrin/Frizzled-4 signaling plays a crucial role in vasculogenesis such as in Norrie disease (ND) and familial exudative vitreoretinopathy (FEVR), which might eventually progress into retinal ischemia and neovascularization (NV; angiogenesis). In addition to ND and FEVR, there are other developmental retinal vascular disorders, namely Coats disease and persistent hyperplastic primary vitreous (PHPV), which share similar fundus images, namely peripheral retinal avascularization and subretinal exudation. As described above, these vitreoretinopathies may also cause retinal ischemia producing a similar threat to patients' vision, although they are not as common as other retinal ischemic disorders, such as central/branch retinal artery occlusion (CRAO/BRAO), central/branch retinal vein occlusion (CRVO/BRVO), glaucoma, diabetic retinopathy (DR) and neovascular age related macular generation (nvAMD). The persistent hypoxia is assumed to be one of the major driving forces of progression of these developmental retinal vascular disorders such as ND.
RGCs and amacrine cells in the inner retina are susceptible to ischemia/reperfusion (I/R). Moreover, vimentin/glial fibrillary acidic protein (GFAP) immunolabeling of Millers is elevated after ischemia; which is associated with RGC number reduction. Overexpression of vascular endothelium growth factor (VEGF), hypoxia inducible factor-1α (HIF-1α), pyruvate kinase M2 (PKM2) and retinoblastoma-binding protein 2 (RBP2) are known to occur concomitantly in the ischemic retina, and further abnormal NV (late neovessel formation) may lead to visual impairments due to edema and hemorrhage. Upregulation of HIF-1α and VEGF can also be observed in the Norrin depleted retina. In addition to VEGF, placental growth factor (PLGF) has been reported to be increased in defined ischemic disorders of the retina/choroid vasculature; thus, downregulation of this factor can be utilized as a biomarker for visual functional outcome and treatment.
DNL (a member of the Orchidae family) is a “vision improving” herb. DNL has also been used as a tonic drug and found to have antipyretic/anti-inflammatory effects and anti-angiogenic (e.g. anti-VEGF/HIF-1α) properties. DNL has several active ingredients with various action mechanisms, including alkaloids (TNFR1 overexpression via inhibiting the p-p38 MAPK and NF-κB pathway), flavonal glycosides (α-glucosidase inhibition), SG-168 and polysaccharides (antioxidation). Furthermore, an anti-angiogenic or anti-oxidative moscatilin is an active component (bibenzyl) of DNL, which might have known (anti-VEGF/HIF-1α, OH radical scavenger, anti-inflammation and anti-apoptosis) and unknown action mechanisms different from those of the above-mentioned components.